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US20060111324A1 - (+)-Ttrans-isomers of (1-phosphonomethoxy-2-alkylcyclopropyl)methyl nucleoside derivatives, process for the preparation of stereoisomers thereof, and use of antiviral agents thereof - Google Patents

(+)-Ttrans-isomers of (1-phosphonomethoxy-2-alkylcyclopropyl)methyl nucleoside derivatives, process for the preparation of stereoisomers thereof, and use of antiviral agents thereof Download PDF

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US20060111324A1
US20060111324A1 US10/528,336 US52833605A US2006111324A1 US 20060111324 A1 US20060111324 A1 US 20060111324A1 US 52833605 A US52833605 A US 52833605A US 2006111324 A1 US2006111324 A1 US 2006111324A1
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compound
formula
group
alkyl
following formula
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Jong-Ryoo Choi
Jae-Taeg Hwang
Dong-Gyu Cho
Kee-Yoon Roh
Chung-Hyung Kim
Chung-Mi Kim
Min-Joon Han
Jeong-Min Kim
Woo-Young Cho
Gyoung-Won Kim
Sin-Byoung Ahn
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LG Chem Ltd
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LG Life Sciences Ltd
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Assigned to LG LIFE SCIENCES LTD. reassignment LG LIFE SCIENCES LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AHN, SIN-BYOUNG, CHO, DONG-GYU, CHO, WOO-YOUNG, CHOI, JONG-RYOO, HAN, MIN-JOON, HWANG, JAE-TAEG, KIM, CHUNG-MI, KIM, CHUN-HYUNG, KIM, GYOUNG-WON, KIM, JEONG-MIN, ROH, KEE-YOON
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • the present invention relates to (+)-trans-isomers of (1-phosphonomethoxy-2-alkylcyclopropyl)methyl nucleoside derivatives represented by the following formula (1):
  • R 1 represents C 1 -C 7 alkyl
  • R 2 and R 3 independently of one another represent hydrogen, or represent C 1 -C 4 -alkyl optionally substituted by one or more substituents selected from a group consisting of halogen (particularly fluorine), C 1 -C 4 -alkoxy, phenoxy, C 7 -C 10 -phenylalkoxy, and C 2 -C 5 -acyloxy, or represent C 2 -C 7 -acyl, C 6 -C 12 -aryl, C 1 -C 7 -alkylaminocarbonyl, di(C 1 -C 7 -alkyl)aminocarbonyl) or C 3 -C 6 -cycloalkylaminocarbonyl, or represent —(CH 2 ) m —OC( ⁇ O)—R 4 wherein m denotes an integer of 1 to 12 and R 4 represents C 1 -C 12 -alkyl, C 2 -C 7 -alkenyl, C 1 -C 5 -alkoxy,
  • X 1 , X 2 , X 3 and X 4 independently of one another represent hydrogen, amino, hydroxy, or halogen, or represent C 1 -C 7 -alkyl, C 1 -C 5 -alkoxy, allyl, hydroxy-C 1 -C 7 -alkyl, phenyl, or phenoxy, each of which is optionally substituted by nitro or C 1 -C 5 -alkoxy, or represent C 6 -C 10 -arylthio which is optionally substituted by nitro, amino, C 1 -C 6 -alkyl, or C 1 -C 4 -alkoxy, or represent C 6 -C 12 -arylamino, C 1 -C 7 -alkylamino, di(C 1 -C 7 -alkyl)amino, C 3 -C 6 -cycloalkylamino, or a structure of
  • n denotes an integer of 1 or 2 and Y 1 represents O, CH 2 , or N—R (R represents C 1 -C 7 -alkyl or C 6 -C 12 -aryl), which are useful as antiviral agents (particularly, against hepatitis B virus), pharmaceutically acceptable salts, hydrates, or solvates thereof, processes for the preparation of stereoisomers thereof, and a composition for the treatment of viral disease (particularly, against hepatitis B virus) comprising (+)-trans-isomer of the compound of formula (1), pharmaceutically acceptable salt, hydrate, or solvate thereof as an active substance.
  • Purine or pyrimidine derivatives have anti-cancer and antiviral activity, and more than 10 kinds of the compounds including AZT, 3TC, and ACV have already been commercialized. Particularly, since acyclic nucleoside phosphonate derivatives show a potent antiviral effect, cidofovir, tenofovir adefovir have been commercialized as antiviral agents, and many compounds including MCC-478 now entered into the clinical trial phases. However, the earlier developed compounds were not perfect in the aspects of toxicity or pharmaceutical activity. Thus, a compound having no toxicity as well as superior activity is still desirable.
  • the compounds of formula (1) have two or more asymmetric carbons, and so have four or more isomers. Isomers of the compounds having asymmetric carbons have different biological properties as well as different physiochemical properties each other. By separating and resolving those isomers, the researches for developing new medicines which are more useful to human being have been recently increased. The earlier research results for those isomers disclosed in patents such as U.S. Pat. No. 4,018,895; U.S. Pat. No. 4,194,009; U.S. Pat. No. 5,618,829; U.S. Pat. No. 5,204,446; U.S. Pat. No.
  • the present inventors have synthesized (1-phosphonomethoxy-2-alkylcyclopropyl)methyl nucleoside derivatives represented by the formula (1), and found processes for preparation of their optical isomers effectively by separating and resolving their mixtures. Also, the present inventors succeeded in discovering that among the stereoisomers of the compounds of formula (1), (+)-trans-isomers are superior to other commercialized or developing medicines in view of pharmaceutical activity as antiviral agents (particularly against hepatitis B virus), and thus completed the present invention.
  • one object of the present invention is to provide (+)-trans-isomers of the compounds of formula (1), pharmaceutically acceptable salts, hydrates, or solvates thereof, which have excellent utility as antiviral agents (particularly, against hepatitis B virus).
  • compositions for the treatment of viral diseases comprising (+)-trans-isomer of the compound of formula (1), pharmaceutically acceptable salt, hydrate, or solvate thereof as an active substance.
  • the compound of formula (l), as represented below, is a type of (1-phosphonomethoxy-2-alkylcyclopropyl)methyl nucleoside derivative having a natural base, such as adenine, guanine, uracil, cytosine, thymine, or derivatives thereof, and having two or more asymmetric carbon atoms:
  • R 1 represents C 1 -C 7 alkyl
  • R 2 and R 3 independently of one another represent hydrogen, or represent C 1 -C 4 -alkyl optionally substituted by one or more substituents selected from a group consisting of halogen (particularly fluorine), C 1 -C 4 -alkoxy, phenoxy, C 7 -C 10 -phenylalkoxy, and C 2 -C 5 -acyloxy, or represent C 2 -C 7 -acyl, C 6 -C 12 -aryl, C 1 -C 7 -alkylaminocarbonyl, di(C 1 -C 7 -alkyl)aminocarbonyl or C 3 -C 6 -cycloalkylaminocarbonyl, or represent —(CH 2 ) m —OC( ⁇ O)—R 4 wherein m denotes an integer of 1 to 12 and R 4 represents C 1 -C 12 --alkyl, C 2 -C 7 -alkenyl, C 1 -C 5 -alkoxy, C 1
  • X 1 , X 2, X 3 and X 4 independently of one another represent hydrogen, amino, hydroxy, or halogen, or represent C 1 -C 7 -alkyl, C 1 -C 5 -alkoxy, allyl, hydroxy-C 1 -C 7 -alkyl, phenyl, or phenoxy, each of which is optionally substituted by nitro or C 1 -C 5 -alkoxy, or represent C 6 -C 10 -arylthio which is optionally substituted by nitro, amino, C 1 -C 6 -alkyl, or C 1 -C 4 -alkoxy, or represent C 6 -C 12 -arylamino, C 1 -C 7 -alkylamino, di(C 1 -C 7 -alkyl)amino, C 3 -C 6 -cycloalkylamino, or a structure of wherein n denotes an integer of 1 or 2 and Y 1 represents O, CH 2 ,
  • the compound according to the present invention can form a pharmaceutically acceptable salt.
  • Such salt includes non-toxic acid addition salt containing pharmaceutically acceptable anion, for example salt with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, etc.; salt with organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc.; or salt with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc., but preferably with sulfuric acid, methanesulfonic acid, hydrohalic acid, etc.
  • inorganic acids such as hydrochloric acid, sulfuric acid,
  • R 1 represents C 1 -C 3 alkyl
  • R 2 and R 3 independently of one another represent hydrogen, or represent C 1 -C 4 -alkyl optionally substituted by one or more substituents selected from a group consisting of fluorine, C 1 -C 4 -alkoxy and phenoxy, or represent —(CH 2 ) m —OC( ⁇ O)—R 4 wherein m denotes an integer of 1 to 12, and R 4 represents C 1 -C 5 -alkyl or C 1 -C 5 -alkoxy, Q represents
  • X 1 represents hydrogen, hydroxy, amino, or 4-methoxyphenylthio
  • X 2 represents hydrogen or amino
  • the compound of formula (1) which is useful as antiviral agents, can be prepared by the following processes.
  • R 1 , R 2 and R 3 are defined as previously described, and L represents a leaving group, preferably methanesulfonyloxy, p-toluenesulfonyloxy, or halogen, is reacted with a compound represented by the following formula (3): QH (3)
  • R 1 and Q are defined as previously described, and R 2′ and R 3′ represent R 2 and R 3 with the exception of hydrogen, respectively, or further the compound thus obtained is subjected to conventional conversions (see: U.S. Pat. Nos. 6,037,335; 5,935,946; and 5,792,756).
  • the reactions may be carried out in a solvent and in the presence of base.
  • the solvent one or more selected from a group consisting of dimethylformamide, dichloromethane, tetrahydrofuran, chloroform, 1-methyl-2-pyrrolidinone, and dimethylacetamide
  • the base one or more selected from a group consisting of sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium t-butoxide, hydrogen bis(trimethylsilyl)amide, sodium amide, cesium carbonate, and potassium bis(trimethylsilyl)amide can be mentioned.
  • the Lewis acid which can be used in the process variant (b) includes trimethylsilylhalide.
  • this compound is subjected to an etherification with an alkylhalide in the presence of base, or is treated with thionyl chloride, oxalyl chloride, or phosphorus pentachloride to produce a dichlorophosphonate derivative which is then reacted with a suitable alcohol or amine to give the desired compound.
  • the phosphonate compound of formula (2) used as a starting material in the above process includes two asymmetric carbons therein, and so has four stereoisomers, each of which is also a novel compound. Therefore, it is another object of the present invention to provide preparation process of the compound of formula (2).
  • P 1 represents an alcohol-protecting group, preferably, benzyl(Bn), tetrahydropiranyl(THP), t-butydiphenylsilyl(TBDPS), or t-butyldimethylsilyl(TBDMS), is reacted with alkyl magnesium halide represented by the following formula (7): R 7 —MgX (7)
  • R 7 represents C 3 -C 7 alkyl and X represents halogen, in the presence of titanium tetraisopropoxide[Ti(OiPr) 4 ],
  • each compound separated in the step (b) is subjected to an etherification in the presence of base with a compound represented by the following formula (10):
  • R 1 , R 2 , R 3 and P 1 are defined as previously described, and
  • the compound of formula (2) wherein R 1 is methyl, ethyl, or propyl, butyl and, pentyl and each of R 2 and R 3 is ethyl or isopropyl can be prepared as follows: (i) an ethylglycolate, the alcohol group of which is protected, [compound (6) in Reaction Scheme 1], is reacted with C 3 -C 7 -alkyl magnesium bromide or C 3 -C 7 -alkyl magnesium chloride [compound (7) in Reaction Scheme 1] in the presence of titanium tetraisopropoxide[Ti(OiPr) 4 ], (ii) the resulting two cyclopropanol diastereoisomers [compounds (8) and (9) in Reaction Scheme 1] are separated with a silica gel column, and then each separated compound is subjected to the ether-forming reaction with dialkylhalomethyl phosphonate [compound (10) in Reaction Scheme 1] to produce
  • Another object of the present invention is to provide processes for the preparation of enantiomers of the compounds of formula (1).
  • R 1 , R 2 and R 3 are defined as previously described, is resolved with a hydrolase to produce compounds represented by the following formula (13a) and (13b), or (14a) and (14b), respectively:
  • each of the compound of formula (13) or (14) that is obtained by removing an alcohol-protecting group in the compound of formula (11) or (12) is resolved with a hydrolase (lipase) to produce the corresponding enantiomer enriched compound of formula (13a) and (13b), or (14a) and (14b), and further an alcohol group in the compound of formula (13a), (13b), (14a) or (14b) thus obtained is replaced with a leaving group (L) to produce compound represented by the following formula (2aa), (2ab), (2ba) or (2bb):
  • an alcohol-protecting group (P 2 ) is introduced into (+)-(methylenecyclopropyl)carbinol or ( ⁇ )-(methylenecyclopropyl)carbinol;
  • an alcohol-protecting group (P 1 ) is introduced into the primary hydroxy group in the compound obtained in the above (bb) step, and an alcohol-protecting group (P 3 ) is introduced into the tertiary hydroxy group to produce a compound represented by the following formulae (15a), (15b), (16a) or (16b):
  • P 1 is defined as previously described
  • P 2 represents an alcohol-protecting group, preferably benzyl, benzoyl, 4-methoxybenzyl, methyloxybenzoyl, methyloxymethyl or trityl
  • P 3 represents an alcohol-protecting group, preferably ester group including 1-methoxyacetyl, acetyl, 2-(trimethylsilyl)-1-ethanesulfonyl, etc.
  • the protecting group P 2 in the resulting compound is removed selectively, a leaving group (L) is introduced, and the compound thus obtained is subjected to a reduction with hydrogen or substitution with C 1 -C 7 -alkyl group,
  • Reaction Scheme 2 is briefly explained below.
  • the compound of formula (2) [compound (4a) in Reaction Scheme 2] is reacted with the compound of formula (3) under the reaction condition as previously described to give the compound of formula (5) [compound (5a) in Reaction Scheme 2].
  • the resulting compound is resolved by a chiral column to give two enantiomer enriched compound [compounds (5b) and (5c) in Reaction Scheme 2].
  • the specific rotation of each compound thus obtained is observed to identify (+)-trans-optical isomer(5b) and ( ⁇ )-trans-optical isomer(5c).
  • Each of optical isomers is treated with trimethylsilylbromide(TMSBr) to give the corresponding enantiomer enriched compounds [compounds (1c) and (1d) in Reaction Scheme 2] of the compound of formula (1a).
  • Reaction Scheme 3 is briefly explained below.
  • the enantiomer enriched compounds [compounds (1c) and (1d) in Reaction Scheme 3] of the compound of formula (1a) can be prepared by using a hydrolase (lipase).
  • An alcohol-protecting group of the compound of formula (11) [compound of formula (11) in Reaction Scheme 3] is removed to give the compound of formula (13) [compound (13) in Reaction Scheme 3].
  • the compound of formula (13) [compound (13) in Reaction Scheme 3] is subjected to the acylation reaction selectively in non-aqueous organic solvent(s) and in the presence of acylation reagent(s) by using the hydrolase (lipase) to give the compounds of formula (13a) [compound (13a) in Reaction Scheme 3] and acylated compound [compound (17) in Reaction Scheme 3]. Further, the acylated compound [compound (17) in Reaction Scheme 3] is hydrolyzed in aqueous solvent(s) by using the hydrolase (lipase) to give the compound of formula (13b) [compound (13b) in Reaction Scheme 3].
  • the compounds of formulae (13a) and (13b) thus obtained are subjected to the procedures as previously described to give the enantiomer enriched compounds of formula (1a), respectively.
  • the specific reaction conditions of the above processes can be referred to the following preparations.
  • the hydrolase (lipase) used in the present invention is meant to an esterlase extracted from Pig liver or Canadida rugosa, or lipase extracted from Canadida antanrctica (fraction A and B), Canadida rugosa, Pseudomonas sp., Porcine pancreas, Humicola sp., Thermomyces sp., or Mucor miehei.
  • the acylation reagent used in the present invention is as follows:
  • R 9 represents hydrogen, C 1 -C 7 -alkyl, C 3 -C 7 -cycloalkyl, or C 5 -C 10 -cycloalkenyl
  • R 10 represents hydrogen, C 1 -C 7 -alkyl, or C 1 -C 7 -alkenyl
  • X 5 and X 6 independently of one another represent C, O or S.
  • R 1 , R 2 , R 3 , P 1 and Q are defined as previously described, and R 11 represents
  • Reaction Scheme 4 is briefly explained below.
  • the enantiomer enriched compound of the compound of formula (1a) [compounds (1c) and (1d) in Reaction Scheme 4] might be prepared through the enantioselective synthesis, another preparation process.
  • (+)-(methylenecyclopropyl)carbinol or ( ⁇ )-(methylenecyclopropyl)carbinol which is well known chiral compounds
  • [compound (18) in Reaction Scheme 4] [references: Journal of Organic Chemistry, 67, 286-289 (2002), Journal of Organic Chemistry, 58, 5915-5917 (1993), Journal of Organic Chemistry, 59, 5483-5484 (1994)] as a starting material
  • the enantiomer enriched compound of the formula (1a) [compound (1c) or (1d) in Reaction Scheme 4] can be prepared as described in Reaction Scheme 4.
  • a protecting group (P 2 ) is introduced into an alcohol group of (+)-(methylenecyclopropyl)carbinol or ( ⁇ )-(methylenecyclopropyl)carbinol [compound (18) in Reaction Scheme 4].
  • Two hydroxyl groups are introduced into a double bond in the resulting compound [compound (19) in Reaction Scheme 4], and other protecting groups (P 1 and P 3 ) are selectively introduced into each hydroxyl group to give the compound of formula (15a) or (15b) [compound (20) in Reaction Scheme 4], respectively.
  • the protecting group (P 2 ) of the compound thus obtained [compound (20) in Reaction Scheme 4] is removed selectively to give the alcoholic compound [compound (21) in Reaction Scheme 4] and the hydroxyl group of the resulting compound [compound (21) in Reaction Scheme 4] is replaced with the leaving group (L) to give the compound [compound (22) in Reaction Scheme 4].
  • the compound thus obtained is subjected to the reductive reaction by using hydrogen, or to the alkyl substitution reaction by using R 8 —M (R 8 represents C 1 -C 6 -alkyl and M represents a metal compound including MgBr and Li) to give the compound [compound (23) in Reaction Scheme 4].
  • the protecting group (P 3 ) of the compound (compound (23) in Reaction Scheme 4) is removed to give the compound of formula (8a) or (8b) [compound (24) in Reaction Scheme 4].
  • the compound of formula (8a) or (8b) [compound (24) in Reaction Scheme 4] is subjected to the etherification with the compound of formula (10) (dialkyl halomethylphosphonate) and the alcohol-protecting group (P 1 ) is removed to obtain the enantiomer enriched compound of formula (13a) or (13b) [compound (13a) or (13b) in Reaction Scheme 4].
  • the compound of formula (13a) or (13b) can be converted to the enantiomer enriched compound of formula (1a) [compound (1c) or (1d) in Reaction Scheme 4] through the same procedure as previously described.
  • the specific reaction conditions of the above process can be referred to the following preparations.
  • the conditions that are used in the preparation processes and the separation and resolution processes of the compounds according to the present invention for example, reactants, solvents, bases, amounts of the reactants used, silica gel column, chiral column, eluents, etc., are not restricted to those explained herein.
  • the compounds of the present invention may be also conveniently prepared, and separated and resolved by optionally combining the various synthetic ways, and the separation and resolution methods described in the present specification or known in the arts, and their combinations can be easily performed by one of ordinary skill in the art to which the present invention pertains.
  • the resulting product may be further separated and purified by usual work-up processes, such as chromatography, recrystallization, distillation, etc.
  • (+)-Trans-isomer of the compound of formula (1) of the present invention can be effectively used as antiviral agents. Therefore, another object of the present invention is to provide a composition for the treatment of viral diseases (particularly, against hepatitis B virus), which comprises as an active ingredient (+)-trans-isomer of the compound of formula (1), pharmaceutically acceptable salt, hydrate or solvate thereof together with the pharmaceutically acceptable carrier(s).
  • the active compounds according to the present invention are preferably administered in an amount ranging generally from 0.01 to 10000 mg, preferably from 0.05 to 100 mg per kg of body weight a day.
  • the total daily dosage may be administered once or over several times.
  • the specific administration dosage for a patient can be varied with the specific compound used, the subject patient's body weight, sex, or hygienic condition, diet, the time or method of administration, excretion rate, mixing ratio of agents, severity of a disease to be treated, etc.
  • the compounds of the present invention may be administered in the form of injections or oral preparations.
  • Injections such as sterilized aqueous or oily suspension for injection, can be prepared according to the known procedure using suitable dispersing agent, wetting agent, or suspending agent.
  • the solvents which can be used for preparing injections include water, Ringer's fluid, and isotonic NaCl solution, and also sterilized fixing oil may be conveniently used as the solvent or suspending media. Any non-stimulative fixing oil including mono-, di-glyceride may be used for this purpose, too. Fatty acid such as oleic acid may be also used for injections.
  • solid preparations for oral administration, capsules, tablets, pills, powders, granules, etc., preferably capsules and tablets, can be mentioned. It is also desirable for tablets and pills to be formulated into enteric-coated preparation.
  • the solid preparations may be prepared by mixing the active compound of (+)-trans-isomer of the compound of formula (1) according to the present invention with at least one carrier selected from a group consisting of inactive diluents, such as sucrose, lactose, starch, etc., lubricants such as magnesium stearate, disintegrating agent, and binding agent.
  • the active compound of (+)-trans-isomer of the compound of formula (1) can be administered in combination with one or more substances selected from the known anti-cancer or antiviral agents.
  • anti-cancer or antiviral agents which can be administered together with the compound of the present invention in such a manner, 5-Fluorouracil, Cisplatin, Doxorubicin, Taxol, Gemcitabine, Lamivudine, etc. can be mentioned.
  • preparations comprising the compound of the present invention are not restricted to those explained above, and may contain any substance useful for the treatment or prevention of cancers or viral diseases.
  • the title compound was prepared as follows: 50 g (0.146 mole) of ethyl 2- ⁇ [t-butyl(diphenyl)silyl]oxy ⁇ acetate was dissolved in 700 ml of tetrahydrofuran (THF), and 30 ml of titaniumtetraisopropoxide was added thereto. To the mixture was slowly added 290 ml of propylmagnesiumchloride (2.OM in THF) at ⁇ 15° C., and the reaction solution was stirred for 12 hours at ambient temperature. 50 ml of saturated ammonium chloride was added to stop the reaction.
  • THF tetrahydrofuran
  • the compound (8-1) prepared in Preparation 1 (7.5 g) was dissolved in 35 ml of dimethylformamide and 9.7 g of diisopropyl bromomethylphosphonate was added thereto, and the resulting mixture was stirred for 10 minutes. To the mixture was slowly added 35 ml of lithium t-butoxide(1.0M in THF) at 50° C., and the mixture was stirred for 4 hours more. Dimethylformamide was removed by distillation under reduced pressure, 40 ml of saturated ammonium chloride was added to the residue, which was then extracted with ethyl acetate.
  • the compound prepared in Preparation 5 (2.3 g) was dissolved in 75 ml of dichloromethane, 1.23 g of triethylamine and 1.2 g of methanesulfonylchloride were added thereto, and the resulting mixture was stirred for 30 minutes at room temperature. Saturated ammonium chloride was added to stop the reaction. The product was extracted with dichloromethane, and the dichloromethane was removed by distillation under reduced pressure to give 2.73 g (yield 94%) of methanesulfonate compound, which was used in the next reaction without any purification.
  • the methanesulfonate thus obtained (430 mg) was dissolved in 18 ml of dimethylformamide, and 57.6mg (60% purity) of sodium hydride and 162 mg of 6-chloroguanine (2-amino-6-chloro-9H-purine) were added thereto.
  • the reaction mixture was refluxed under heating for 4 hours. Saturated ammonium chloride was added to stop the reaction.
  • the racemate prepared in Preparation 5 (51 g) was dissolved in 200 ml of toluene, 1.5 g of lipase ( Canadida antanrctica B, immobilised, Novozyme 435), and 11.8 ml of vinyl acetate were added thereto, and the resulting mixture was stirred for 40 hours at ambient temperature.
  • the solvent was removed by distillation under reduced pressure, and the mixture compounds (13a) and (17) were separated by a chromatography method to give 17.7 g of the compound (13a) and 38.4 g of the compound (17).
  • the compound (17) was added to 100 ml of phosphate buffer (0.3M, pH 7.2), the solution was hydrolyzed by 1.54 g of Novozyme 435 as much as 60%, and extracted with an organic solvent. And, the solvent was removed by distillation under reduced pressure, and the mixture was separated to give 16.6 g of the compound [the compound (13b) in Reaction Scheme 3] and 18.92 g of the compound [the compound (17) in Reaction Scheme 3].
  • the compound [the compound (17) in Reaction Scheme 3] was hydrolyzed according to the same procedure as the above, and the resulting mixture was separated to give 6.2 g of the compound [the compound (13b) in Reaction Scheme 3] and 8.3 g of the compound [the compound (17) in Reaction Scheme 3].
  • the compound prepared in Preparation 20 (200 mg) was dissolved in water/THF (5 ml/5 ml), and 1 ml of OsO4 (Osmium tetroside, 2.5 wt % solution in t-butanol) and NMO (4-methyl morpholine N-oxide) were added thereto. After stirring the mixture for 24 hours, water (20 ml) and methylenedichloride (50 ml) were added thereto, and the organic layer was separated.
  • OsO4 Oxmium tetroside, 2.5 wt % solution in t-butanol
  • NMO 4-methyl morpholine N-oxide
  • the compound prepared in Preparation 23 (200 mg) was dissolved in methanol (20 ml), and 40 mg of 10% Pd on Carbon was added thereto. The resulting mixture was reduced with hydrogen gas under 1 atm for 24 hours. The 10% Pd on Carbon (50 mg) was further added thereto, and the resulting mixture was additionally reduced for 24 hours. The Pd on Carbon was removed by celite, the residual solution was removed by distillation under reduced pressure, and the residue was purified by a silica gel column chromatography (eluent: ethylacetate/n-hexane: 1/2, v/v) to give 160 mg (yield 98%) of the title compound.
  • the compound prepared in Preparation 24 (150 mg) was dissolved in 10 ml, of acetonitrile (AN), and 230 mg of triphenylphosphine (PPh 3 ) and 240 mg of carbontetrabromide (CBr 4 ) were slowly added dropwise thereto at 0° C. The resulting mixture was stirred for 1 hours at ambient temperature. Water (20 ml) and diethylether (50 ml) were added thereto. The organic layer therein was separated and removed by distillation under reduced pressure. The residue was purified by a silica gel column chromatography (eluent: ethylacetate/n-hexane: 1/8, v/v) to give 130 mg (yield 76%) of the title compound.
  • AN acetonitrile
  • PPh 3 triphenylphosphine
  • CBr 4 carbontetrabromide
  • the compound prepared in Preparation 25 (120 mg) was dissolved in methanol (20 ml), and 20 mg of 10% Pd on Carbon was added thereto. The resulting mixture was reduced with hydrogen gas under 1 atm for 24 hours. The 10% Pd on Carbon (50 mg) was further added, and the resulting mixture was additionally reduced for 24 hours. The Pd on Carbon was removed by celite, the residual solution was removed by distillation under reduced pressure, and the residue was purified by a silica gel column chromatography (eluent: ethylacetate/n-hexane: 1/8, v/v) to give 80 mg (yield 79%) of the title compound.
  • the compound prepared in Preparation 27 (9 mg) was dissolved in 0.5 ml of dimethylformamide(DMF) solution in which 17.0 mg of diisopropyl bromomethylphosphonate was dissolved, and 5 mg of lithiumiodide (LiI) was added thereto.
  • the lithium t-butoxide (LiOtBu) solution (0.11 ml) that 800 mg of lithium t-butoxide was dissolved in 10 ml of THF and 10 ml of DMF, was slowly added at 60-65° C. to the above solution in which the compound was dissolved. The resulting mixture was stirred for 10 hours at the same temperature.
  • (+)-trans-optical isomer was resolved by a chiral column to obtain (+)-trans-optical isomer and ( ⁇ )-trans-optical isomer.
  • (+)-Trans-optical isomer (40 mg) resolved in Example 1 was dissolved in 8 ml of dichloromethane, and 285 mg of trimethylsilylbromide (TMSBr) was added thereto to reflux for 4 hours.
  • Dichloromethane was distilled under reduced pressure to obtain a solid.
  • the resulting solid was dissolved in 1N-HCl (10 ml) to reflux for 4 hours.
  • water used as a solvent was distilled under reduced pressure, and the residue was solidified from methanol/ether (10/1) to obtain 25.4 mg (yield 83%) of the title compound as white solid.
  • (+)-trans-optical isomer As described in the above Reaction Scheme 2, racemates were resolved by a chiral column to obtain (+)-trans-optical isomer and ( ⁇ )-trans-optical isomer.
  • (+)-Trans-optical isomer (40 mg) resolved in Example 3 was reacted according to the same procedure as Example 2 to obtain 25.0 mg of the title compound as white solid.
  • (+)-Optical isomer (5b-1, 1.8 g) prepared in Example 1 was dissolved in 20 ml of methanol, 0.46 g of triethylamine (TEA) and 0.18 g of 10% Pd on C were added thereto, and the resulting mixture was reduced in hydrogen (1 atm) at 25° C. for 18 hours.
  • the reactant was passed through cellite to remove Pd, and the obtained filtrate was distillated under reduced pressure to obtain the desired 6-dioxyguanidine derivative in 100% yield.
  • (+)-Optical isomer (5b-4, 400 mg) prepared in Example 3 was reacted according to the same procedure as Example 5 to obtain 270 mg of the title compound.
  • 6-Chloroguanidine derivative (48mg) of the compound prepared in Preparation 13 was dissolved in 9 ml of ethanol, and 140 mg of triethylamine and 290 mg of 4-methoxythiocresole were added thereto. The resulting mixture was reacted under the reflux condition for 24 hours, and the reaction was completed by adding 20 ml of water. The reactant was distilled under reduced pressure to remove methanol, and the distilled reactant was extracted with dichloromethane and the extracting liquid was removed by distilling under reduced pressure. The residue was purified by a silica gel column to obtain the compound (40 mg), guanine of which 6-position was substituted by 4-methoxyphenylthio.
  • the compound (600 mg) prepared in Example 5 was added to 5 ml of 1-methyl-2-pyrrolidinone. The mixture was heated to 60° C. and stirred for 30 minutes. To the resulting reactant, 0.58 g of triethylaniine and 0.86 g of chloromethylpivalate were added and the resulting mixture was stirred for 27 hours. The reactant was extracted with ethylacetate after lowering its temperature to 20° C. and completing the reaction by adding 20 ml of water. The reactant was distilled under reduced pressure to remove the extracting liquid. The residue was purified by a silica gel column chromatography to obtain 250 mg (yield 24%) of the title compound.
  • Example 5 The compound (0.98 g) prepared in Example 5 was added to 5 ml of 1-methyl-2-pyrrolidinone. The mixture was heated to 50° C. and stirred for 30 minutes. To the resulting reactant, 0.96 g of triethylamine and 1.44 g of chloromethylisopropylcarbonate were added and the resulting mixture was stirred for 3 hours. The reactant was extracted with ethylacetate after lowering its temperature to 20° C. and completing the reaction by adding 20 ml of water. The reactant was distilled under reduced pressure to remove the extracting liquid. The residue was purified by a silica gel column chromatography to obtain 270 mg (yield 16%) of the title compound.
  • 6-Chloroguanidine derivative (48mg), the (+)-optical isomer compound prepared in Example 1, was dissolved in 9 ml of ethanol, and 140 mg of triethylamine and 290 mg of 4-methoxythiocresole were added thereto. The resulting mixture was reacted under the reflux condition for 24 hours, and the reaction was completed by adding 20 ml of water. The reactant was distilled under reduced pressure to remove methanol, and the distilled reactant was extracted with dichloromethane and the extracting liquid was removed by distilling under reduced pressure. The residue was purified by a silica gel column to obtain the compound, guanine of which 6-position was substituted by 4-methoxyphenylthio.
  • 6-Chloroguanidine derivative (48 mg), the compound prepared in Preparation 17, was dissolved in 9 ml of ethanol, and 140 mg of triethylamine and 290 mg of 4-nitrothiocresole were added thereto. The resulting mixture was reacted under the reflux condition for 24 hours, and the reaction was completed by adding 20 ml of water. The reactant was distilled under reduced pressure to remove methanol, and the distilled reactant was extracted with dichloromethane and the extracting liquid was removed by distilling under reduced pressure. The residue was purified by a silica gel column to obtain the compound (32 mg), guanine of which 6-position was substituted by 4-nitrophenylthio.
  • the compound of the present invention exhibits a potent pharmacological effect to a hepatitis B cell line, HepG2.2.15, and a transgenic mouse, widely used for development of a therapeutic agent against hepatitis B, when intravenously or orally administered.
  • the experimental procedures and results are described below.
  • HBV Hepatitis B Virus
  • HepG2.2.15 cell (M. A Shells et al., P.N.A.S. 84, 1005(1987)), a hepatocarcinoma cell line producing hepatitis B virus, was cultured in DMEM medium(GIBCO BRL, #430-2200) containing 10% FBS(Fetus bovine serum, GIBCO BRL, #16000-044), 1% ABAM (Antibiotic-Antimycotic, GIBCO BRL, #16000-028) and 400 ⁇ g/ml of geneticin(Sigma, #G-9516) in a T-75 flask under the conditions of 5% CO 2 incubator and 37° C. by dividing in a ratio of 1:3 at an interval of 3 days.
  • the cells were distributed into a 96-well plate in the amount of 4 ⁇ 10 4 /well and then when 80-90% of cell density was achieved, the old medium was changed with 200 ⁇ l of DMEM medium containing 2% FBS, 1% ABAM and 400 ⁇ g/ml of geneticin.
  • the drug solution was sequentially diluted five-fold each time, from 100 ⁇ M to 0.16 ⁇ M. In order to minimize an experimental error, each treatment was repeated 2-3 times for the respective drugs.
  • the medium was changed every two days. On 10 days after the treatment with drug, 100 ⁇ l of the medium was collected and the degree of inhibition of viral replication by drugs was determined through quantitative PCR (Polymerase Chain Reaction).
  • MTT Thiazolyl Blue Tetrazolium Bromide, Amresco, #0793-5G
  • the degree of inhibition by drugs on the replication of hepatitis B virus was determined by using the cell culture solution collected on 10th day after the treatment with the drug.
  • the cell culture solution treated with each drug was diluted ten-fold with distilled water and subjected to a pretreatment to destroy the cells by heating them for 15 minutes at 95° C.
  • the 2001-base position that is conserved in all sub-strain of hepatitis B virus and 2319-base position that is between the core antigen gene and polymerase gene were used as 5′-end and 3′-end primer, respectively.
  • the amount of genomic DNA of hepatitis B virus was quantified, and the inhibitory effect by drugs on the replication of hepatitis B virus was determined on the basis thereof.
  • the cell culture solution of hepatitis B virus that was not treated with drug was sequentially diluted and amplified through the PCR.
  • the amplified DNA was subjected to electrophoresis on 2% agarose gel and stained with ethidium bromide (EtBr) to be analyzed by IS-1000 (Innotech Scientific Corporation) Digital Imaging System. Analysis of the cell culture solution treated with drug was then carried out by using the dilution fold in the range where linearity is maintained.
  • the DNA obtained from the group treated with drug was amplified through the same PCR method, subjected to electrophoresis on 2% agarose gel, stained with ethidium bromide, and analyzed by IS-1000.
  • the compounds were administered via subcutaneous and oral routes in the following animal test.
  • test compounds were administered to 4-5 week old HBV transgenic mice, which were obtained from FVB strain mice according to a method described in a reference (see, Jone D. Morrey, Kevin W. Bailey, Brent E. Korba, Robert W. Sidwell, Utilization of mice replicating high levels of hepatitis B virus for antiviral evaluation of lamivudine Antiviral research, 1999, 42, 97-108), subcutaneously for 9 days in the amount of 10 mg/kg/day and orally for 9 days in the amount of 10, 2 and 0.4 mg/kg/day, once a day, respectively (the same number of males and females were used). Blood was collected from the tail of the mouse and 5 t ⁇ l of serum was obtained during or after the administration of the drug.
  • HBV DNA was taken from the pretreated solution.
  • the DNA was amplified by the PCR (Polymerase Chain Reaction) in the presence of 4 ⁇ l of 10 ⁇ buffer (Perkin Elmer), 0.8 ⁇ l of 10 mM dNTP, 500 ng of the same HBV primers as used in Experiment 1, 2, 125 mM of MgCl 2 , DMSO and Taq polymerase.
  • the amount of HBV DNA was analyzed by electrophoresis in order to evaluate a pharmacological effect of the compound of the present invention. The results are described in the following Table 3.
  • mice showing pharmacological effect ⁇ means the mice whose blood does not contain HBV DNA.
  • TABLE 3 Compound No. Amount(mg/kg/day) Result* Administration 2 10 4/4 subcutaneous 6 1 5/5 oral 7 1 5/5 oral 8 1 2/5 oral *The result means ⁇ number of mice showing pharmacological effect / number of total mice ⁇
  • the compound of the present invention shows a potent hepatitis B therapeutic effect in the tested animals when orally or subcutaneously administered. Since Compounds 6 and 7 of the (+)-optical isomers exhibit very excellent pharmacological effect when they are orally administrated at 1 mpk or less, it is expected that the compounds of the present invention may be used very effectively for the treatment of hepatitis B.

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US20040063668A1 (en) * 2001-01-19 2004-04-01 Jong-Ryoo Choi Novel acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same
US20090169504A1 (en) * 2006-12-28 2009-07-02 Idenix Pharmaceuticals, Inc Compounds and Pharmaceutical compositions for the treatment of Viral infections
US20090187019A1 (en) * 2004-07-02 2009-07-23 Lg Life Science Ltd. Process for preparing diisopropyl((1-(hydroxymethyl)-cyclopropyl)oxy)methylphosphonate
US20100003217A1 (en) * 2008-07-02 2010-01-07 Erika Cretton-Scott Compounds and Pharmaceutical Compositions for the Treatment of Viral Infections
WO2012154321A1 (en) 2011-03-31 2012-11-15 Idenix Pharmaceuticals, Inc. Compounds and pharmaceutical compositions for the treatment of viral infections
WO2013039920A1 (en) 2011-09-12 2013-03-21 Idenix Pharmaceuticals, Inc. Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections
US8680071B2 (en) 2010-04-01 2014-03-25 Idenix Pharmaceuticals, Inc. Compounds and pharmaceutical compositions for the treatment of viral infections

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US5977061A (en) * 1995-04-21 1999-11-02 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic N6 - substituted nucleotide analagues and their use
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US20040063668A1 (en) * 2001-01-19 2004-04-01 Jong-Ryoo Choi Novel acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same
US7157448B2 (en) * 2001-01-19 2007-01-02 Lg Life Sciences Ltd. Acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same
US20100305364A1 (en) * 2004-07-02 2010-12-02 Suk-Kyoon Yoon Process for preparing diisopropyl((1-(hydroxymethyl)-cyclopropyl)oxy)methylphosphonate
US20090187019A1 (en) * 2004-07-02 2009-07-23 Lg Life Science Ltd. Process for preparing diisopropyl((1-(hydroxymethyl)-cyclopropyl)oxy)methylphosphonate
US7795463B2 (en) * 2004-07-02 2010-09-14 Lg Life Sciences Ltd. Process for preparing diisopropyl((1-(hydroxymethyl)-cyclopropyl)oxy)methylphosphonate
US20090169504A1 (en) * 2006-12-28 2009-07-02 Idenix Pharmaceuticals, Inc Compounds and Pharmaceutical compositions for the treatment of Viral infections
US7902202B2 (en) 2006-12-28 2011-03-08 Idenix Pharmaceuticals, Inc. Compounds and pharmaceutical compositions for the treatment of viral infections
US7951789B2 (en) 2006-12-28 2011-05-31 Idenix Pharmaceuticals, Inc. Compounds and pharmaceutical compositions for the treatment of viral infections
US8691788B2 (en) 2006-12-28 2014-04-08 Idenix Pharmaceuticals, Inc. Compounds and pharmaceutical compositions for the treatment of viral infections
US9249173B2 (en) 2006-12-28 2016-02-02 Idenix Pharmaceuticals, Llc Compounds and pharmaceutical compositions for the treatment of viral infections
US20100003217A1 (en) * 2008-07-02 2010-01-07 Erika Cretton-Scott Compounds and Pharmaceutical Compositions for the Treatment of Viral Infections
US8680071B2 (en) 2010-04-01 2014-03-25 Idenix Pharmaceuticals, Inc. Compounds and pharmaceutical compositions for the treatment of viral infections
WO2012154321A1 (en) 2011-03-31 2012-11-15 Idenix Pharmaceuticals, Inc. Compounds and pharmaceutical compositions for the treatment of viral infections
US9243025B2 (en) 2011-03-31 2016-01-26 Idenix Pharmaceuticals, Llc Compounds and pharmaceutical compositions for the treatment of viral infections
WO2013039920A1 (en) 2011-09-12 2013-03-21 Idenix Pharmaceuticals, Inc. Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections

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